Targets for MRD Detection in Cases Lacking Fusion Genes

A number of potential targets have been proposed for PCR-based approaches to MRD detection for cases of AML lacking a suitable fusion gene marker. These include detection of mutant forms of NPM1, which occur in over half of normal karyotype AML. Preliminary evidence using RQ-PCR assays indicates, that NPM1 mutation is likely to provide a sensitive, specific and stable target for MRD detection.31,32 This contrasts with FLT3 mutations which are not always stable over the time course of the disease, raising concern over the value of these as reliable targets for MRD detection.33 Nevertheless, these findings provide further evidence for the hypothesis that FLT3 mutations are secondary events in the pathogenesis of AML. There is considerable interest in whether RNA-based assays that involve detection of transcripts that are overexpressed in leukemia, for example, WT1, could be of value as MRD markers in patients lacking a fusion gene target. However, to establish the role of such markers it is critical to determine the level of expression at diagnosis relative to endogenous control transcripts, for example, ABL, on an individual patient basis. Other key factors that must be taken into account are the range of expression levels documented in normal peripheral blood and bone marrow, as well as levels of expression in the context of regeneration following myelosuppressive therapy. Such information is vital to establish the sensitivity of the assay in any given patient and the likely clinical utility of any novel marker for MRD assessment.